All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
CVD and CNS disorders caused by microbial infection, external mechanical force to the brain (e.g. traumatic brain injury), stroke, drug abuse, brain tumor, or neurodegenerative diseases, remain to be the world's leading causes of death and disabilities despite aggressive researches. The brain is the most delicate organ of the body. It is protected by the blood-brain barrier (BBB). Diseases associated with neurovascular unit (NVU) or BBB injuries account for more hospitalizations and prolonged care than almost all other diseases combined. Patients experiencing devastating CVD or CNS diseases far outnumber those suffering and dying from all types of systemic cancers or heart diseases. Over one-third of the entire population will experience a CNS disorder during their lifetime. CVD is most commonly associated with high blood pressure (HBP, hypertension). About one in three American adults (32%) has HBP, whereas another 1 in 3 American adults has prehypertension. The incidence of CVD and CNS disorders increases with age.
NeuroAIDS as a form of microbial infection of the brain is a significant cause of CNS disorder. The prevalence of NeuroAIDS has increased recently despite advances in highly active antiretroviral therapy. This is mainly due to the inability of antiretroviral drugs to cross the BBB and the role of CNS as the reservoir for HIV-1, a virus that is capable of freely migrating in and out of the brain. The incidence of NeuroAIDS is higher or accelerated among the aging populations and drug users.
Quantitative evaluation of NVU or BBB damages has been one of the most challenging issues in researching CVD or CNS disorders caused by microbial and non-microbial insults. Successful isolation and cultivation of brain microvascular endothelial cells (BMECs), which are the relevant in vitro model of the NVU or BBB, has enabled both molecular characterization and genome-wide analysis of the pathogenic mechanisms of BBB injuries attributable to microbial or non-microbial factors in vitro. However, it is difficult to carry out genome-wide, noninvasive evaluation of NVU or BBB injuries in vivo.
A variety of methods have been used to evaluate the function of the NVU or BBB in vivo. Leakage of peripheral proteins such as fibrinogen and albumin into the CNS has been used to evaluate BBB permeability associated with viral encephalitis and other CNS infection. While these techniques have the advantage of using endogenous proteins, the NVU or BBB injury may not correlate well with the protein levels in CNS due to certain nonspecific effects. Recent studies show that there are no blood tests utilizing a molecular biomarker that can accurately determine the presence or the severity of cerebrovascular disorders (CVD) such as traumatic brain injury (TBI) because no clinical tools are available for measuring glymphatic-derived convective bulk flow of the molecular movements within the brain's interstitium.
Recently, magnetic resonance (MRI)-based molecular imaging technologies have gained increasing attention in neuroscience. Although an increasing number of synthesized molecular imaging agents have been tested in vitro, very few have been validated in the brains of live animals. The major challenges in molecular neuroimaging approaches are the poor ability of delivering agents across the BBB. Other methods involve the injection of dyes, such as Evans blue and sodium fluorescein, into a variety of animal model systems for evaluation of BBB permeability. The main limitation of these techniques is that they cannot be used in humans.
Despite the identification of hundreds of molecular markers by preclinical and clinical researches over the past few decades, there is currently no blood test clinically available for objective evaluation of the presence or severity of NVU or BBB injuries. Therefore, there exists a need for non-invasive biomarkers to address the problem of the diagnosis, prognosis, prevention, and treatment of the CVD or CNS disorders.